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Delirium - Causes and Pathogenesis
Medical expert of the article
Last reviewed: 06.07.2025
Causes of delirium
Determining the cause of delirium is based on the clinical interpretation of the data that has been obtained. The main categories of disorders that must be excluded include infections, metabolic and endocrine disorders, trauma, nutritional or exogenous influences, neoplasms, the effects of drugs or substance abuse. The DSM-IV identifies the following categories of conditions that cause delirium: general diseases, intoxication or withdrawal, delirium of multiple etiologies, which arise under the influence of several causes. Most often, the development of delirium depends on a combination of many provoking factors. Not all causes of delirium are reversible or become known.
Delirium due to intoxication or withdrawal of psychoactive substances
Intoxication delirium is diagnosed when it occurs as a result of the introduction of a drug or other chemical substance. The goal of treatment is to remove the substance from the body. The substance causing the delirium may be identified by history, physical examination, or laboratory testing, such as toxicology screening. Familiarity with the most common intoxication syndromes may be important, as this will allow more targeted laboratory testing, in particular, to include testing for additional agents in the screening program. Advice can be obtained from a local poison control center, which has a database of reactions to the most common drugs, chemicals, and plants. Once the suspected agent causing the delirium is identified, appropriate treatment can be initiated. There are developed methods for treating overdoses of substances such as acetaminophen, aspirin, organic solvents, ethylene glycol, opioids, benzodiazepines, barbiturates, and anticholinergics. The physician should also be familiar with the most common substances that are abused and can cause delirium. These include cocaine, phencyclidine, heroin, alcohol, nitrous oxide, speed, marijuana, and ecstasy. Opioid-induced delirium can be treated with naloxone, an opioid receptor antagonist. The drug's effect is often temporary and can cause withdrawal symptoms. During delirium or intoxication, opioid abusers have an increased risk of contracting HIV through shared needles or sexual intercourse.
Benzodiazepine intoxication may also trigger delirium. In addition to supportive measures, treatment may include the benzodiazepine receptor antagonist flumenesil. When treating benzodiazepine, alcohol, or opioid overdose, it is important to avoid the development of withdrawal symptoms, which may themselves trigger delirium. Treatment should include controlled detoxification to prevent worsening delirium or even death, which may be associated with the development of withdrawal symptoms.
In alcohol and benzodiazepine withdrawal, the drug that caused the delirium is replaced with a benzodiazepine and the dose is gradually reduced. The benzodiazepine dose should be brought to a level that prevents hyperactivity of the autonomic nervous system. In addition, in alcohol withdrawal, the patient should be prescribed thiamine, folic acid, and multivitamins. Benzodiazepine detoxification is often carried out more slowly than alcohol detoxification. Opioid withdrawal syndrome manifests itself with flu-like symptoms and may be accompanied by delirium. In this case, they resort to gradual withdrawal of the opioid or its replacement with a long-acting opioid, such as methadone. Treatment of addiction to psychoactive substances also includes non-drug measures. An example is the 12-step program used by Alcoholics Anonymous and Narcotics Anonymous.
Pathogenesis of delirium
Although delirium was first described in medical literature at least 2,500 years ago, the pathogenesis of this syndrome remains unclear, although there are several theories about its origin.
Neurochemical changes
Since the cholinergic system is involved in attention, wakefulness, memory, and rapid eye movement sleep, a decrease in its activity may be a factor in the pathogenesis of delirium. Moreover, it has been shown that anticholinergics weaken memory and concentration and can cause delirium, with their serum levels increasing during delirium and decreasing during its resolution. Administration of atropine to laboratory animals causes behavioral and EEG changes, indicating an important role of the cholinergic system in the development of delirium. Cognitive impairment caused by anticholinergics can be relieved by acetylcholinesterase inhibitors - physostigmine, donepezil, or ENA-713.
The dopaminergic system may also play a role in the pathogenesis of delirium. Neuroleptics block the activity of the dopaminergic system and reduce the symptoms of delirium. Drugs that enhance dopaminergic activity, such as levodopa, bupropion, and amantadine, can cause delirium as a side effect. Hypoxia, which can also cause delirium, increases extracellular dopamine levels.
In the cerebrospinal fluid, the level of somatostatin-like reactivity and beta-endorphin in patients with delirium was lower than in healthy individuals of the same age. This decrease in protein concentration persisted for the following year. However, since these patients had some degree of dementia, this factor may be the cause of the decrease in the level of beta-endorphin and somatostatin in the cerebrospinal fluid.
Neuronal damage
Changes in oxidative metabolism may result in neuronal damage. In one report, EEG changes associated with delirium regressed in patients with hypoxia during oxygen treatment, in patients with hypoglycemia after glucose administration, and in patients with anemia after blood transfusion. Subsequent studies have not directly examined oxidative metabolism processes in delirium. Hypoxia and hypoxemia reduce the synthesis and release of acetylcholine, which may explain the association of changes in oxidative metabolism with delirium.
Changes in glutamate transmission in the brain can lead to the development of apoptosis and neuronal damage. Thus, excessive activation of NMDA receptors causes cell death, and phencyclidine can cause delirium by blocking these receptors. Ketamine, which also blocks NMDA receptors, affects the level of consciousness. In the future, glutamate NMDA receptor agonists may be used to treat delirium.
Damage to the blood-brain barrier can also lead to neuronal damage and delirium. Intraventricular administration of interleukin-1 to experimental animals resulted in the development of clinical and EEG manifestations of delirium. Delirium often occurs in patients undergoing chemotherapy with interleukin-2, lymphokine-activated killer cells, or alpha interferon. The mechanism of delirium development is presumably associated with damage to the capillary endothelium and the blood-brain barrier.
Studying the mechanisms of delirium development in hepatic encephalopathy may help to clarify the pathogenesis of this condition. They include accumulation of unmetabolized ammonia, production of false neurotransmitters, activation of GABA receptors, changes in cerebral metabolism and Na+/K+/ATPase activity. Manganese deposition in the basal ganglia, zinc deficiency, and changes in the activity of urea cycle enzymes may also play a role. The most effective approach to treating hepatic encephalopathy is to enhance ammonia metabolism or reduce its production.